The mdm-2 gene is induced in response to UV light in a p53-dependent manner.

Abstract

Irradiation of mammalian cells with UV light results in a dose-dependent accumulation of the p53 tumorsuppressor gene product that is evident within 2 hr. UV treatment causes a dramatic increase in p53-specific transcriptional transactivation activity and an increase in expression of the p53-responsive gene mdm-2. UV-stimulated mdm-2 expression is not directy correlated with the level of p53 protein in a cell because mdm-2 induction is delayed at high UV doses even though p53 levels rise almost immediately. Cells lacking p53 protein do not respond to UV by increasing their expression of mdm-2. The delayed induction of mdm-2 at high UV doses suggests that, in addition to p53 protein levels, other factors contribute to the regulation of mdm-2 expression following UV treatment. The time of induction of mdm-2 in cells treated with UV light correlates with recovery of normal rates of DNA synthesis, presumably after DNA repair. These data indicate a possible role for mdm-2 in cell cycle progression.Mammalian cells respond to irradiation with UV light by transiently decreasing both RNA and DNA synthesis and by inducing expression of several genes whose products are thought to have protective effects against DNA damage (1). The regulation of these UV response genes appears to be mediated by several transcription factors which function after UV exposure (2). The p53 tumor-suppressor gene product is a transcription factor (3,4) that also appears to be involved in the response to UV light. The p53 protein levels increase due to the stabilization ofthis protein in both murine (5, 6) and human (7,8) cells treated with UV light. Although the role of p53 in the response to UV light has not been fully characterized, this tumor-suppressor protein has been shown to act as a cell cycle checkpoint in the response to y irradiation (9,10). fy irradiation induces both a G1 and a G2 phase-specific cell cycle block, and expression of wild-type p53 is necessary for the G1 but not the G2 block. The specific DNA-binding activity of p53 is increased after y irradiation and a DNA damage-inducible, growth arrest-specific gene, GADD45, has been shown to contain a p53 response element (10).Characterization of the role of p53 in the response to 'y irradiation led to the hypothesis that p53 acts as a cell cycle checkpoint, causing a delay in the G1 phase of the cycle during which damage is thought to be repaired (9, 10). It seemed likely that p53 might also act as a checkpoint in the response of cells to UV exposure. In addition, Zhan et al. (8) have recently shown that p53 transcriptional transactivation activity is increased in human cells exposed to UV light. Possible targets for p53 transcriptional transactivation activity in the UV response are the GADD45 gene, which was isolated as a UV response gene (11), and the mdm-2 gene. p53 and mdm-2 appear to form a feedback control loop: while p53The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" ...

Induction of BCL2 family member MCL1 as an early response to DNA damage

“…MCL1) and death-promoting molecules (e.g. BAX), cells exposed to IR exhibit an upregulation of both p53 and MDM2, the latter being a negative regulator of p53 Chen et al, 1994;Finlay, 1993;Momand et al, 1992;Oliner et al, 1992;Perry et al, 1993;Wu et al, 1993;Xiong et al, 1993). In this case, it has been postulated that MDM2 might serve as part of a feedback loop, limiting the duration of growth-arrest by p53.…”

“…As expected from the involvement of p53 in this response, downstream targets of p53 appear to be involved (Kastan et al, 1992;Miyashita and Reed, 1995). These targets include GADD45, a growth-arrest and DNA damage-inducible gene, p21 CIP1/WAF1 , an inhibitor of cyclin-dependent kinases, and MDM2, a gene encoding a product that interacts with p53 (El-Deiry et al, 1993;Harper et al, 1993;Kastan et al, 1992;Miyashita and Reed, 1995;Noda et al, 1994;Perry et al, 1993;Zhan et al, 1994aZhan et al, ,b, 1995Selvakumaran et al, 1994;Miyashita et al, 1994). Gadd45 and p21 Cip1/Waf1 cause growth suppression and thus may serve as downstream e ectors of the growth-arrest response (Xiong et al, 1993;Zhan et al, 1994cZhan et al, , 1995.…”

Mdm2: keeping p53 under control

“…After repair of DNA damage, accumulated Mdm2 rapidly degrades p53. See text for further details C127 cells to UV-C irradiation was investigated (Perry et al, 1993). The induction of Mdm2 by u.v.…”

“…In a study by Perry and colleagues a large proportion of both Mdm2 and p53 seemed to be uncomplexed, which suggested that the ability of both proteins to interact with each other could e ectively be regulated (Perry et al, 1993). Complex formation was studied in more detail by Momand and Zambetti who found that Mdm2 was bound to a variable subpopulation of p53 in di erent cell types: all p53 was bound in 3T3DM cells while no detectable Mdm2 was bound in Balb/c3T3 cells or normal ®broblasts (Momand and Zambetti, 1996).…”

Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-κB and Myc/Max

“…p53 was found to function as a transcriptional regulator of several cellular genes: It transactivates genes like GADD45 (Kastan et al, 1992), p21 , MDM2 (Perry et al, 1993;Chen et al, 1994), bax (Miyashita and Reed, 1995) and cyclin G (Okamoto and Beach, 1994) and transrepresses TATAmediated transcription (Mack et al, 1993) of genes such as PCNA and several viral promoters Deb et al, 1992). Both, the expression and the activity of the p53 protein are tightly controlled.…”